eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors Ethical standards and procedures
SCImago Journal & Country Rank
vol. 8

State of the art paper
Therapeutic options for severe asthma

Jilcy Mathew
Wilbert S. Aronow
Dipak Chandy

Arch Med Sci 2012; 8, 4: 589-597
Online publish date: 2012/09/08
Article file
- Therapeutic options.pdf  [0.10 MB]
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero


Asthma is a chronic inflammatory disorder of the airways associated with bronchial hyper-responsiveness (BHR), reversible airflow limitation and recurrent symptoms of wheezing, chest tightness and cough. Etiologies includes genetic and environmental factors that together create a state of persistent inflammation of the lower respiratory tract that can be worsened by various trigger factors like allergen exposure, smoking, drugs and exercise. Cross-sectional surveys estimate that the prevalence of asthma has increased by about 38% in the past two decades [1]. Explanations for this increased prevalence include a parallel rise in the prevalence of obesity [2] and allergic rhinitis1, as well as the levels of air pollution [3].

According to the WHO/NHLBI Global Initiative for Asthma (GINA) guidelines, asthma is best classified according to the level of clinical control into controlled, poorly controlled and uncontrolled [4]. Previously asthma was classified as mild, moderate and severe based on the severity of symptoms, degree of lung impairment and amount of medication required. While mild and moderate asthma can be successfully managed with traditional therapy using 2-agonists and corticosteroids [5], severe asthma remains a clinically, socially and economically difficult condition to manage, with patients suffering from frequent exacerbations and intolerable symptoms, leading to significantly higher healthcare costs [6, 7] compared to their less severe counterparts.

Various criteria for defining severe asthma have been put forth by many organizations and clinicians worldwide. For the purpose of this paper, severe asthma shall be understood to refer to the state of asthma in which clinical symptoms of asthma persist in an uncontrolled manner, despite the highest level of therapy advocated in the WHO/NHLBI GINA guidelines [5]. Thus, severe asthma is a broad term and encompasses “difficult asthma”, “uncontrolled asthma” and “refractory asthma”. As multiple definitions exist, the prevalence of severe asthma has been difficult to determine. However, it can be estimated that approximately 3% [8, 9] of the asthma population suffers from this condition. Although this may seem a small proportion, the magnitude of clinical difficulty to those managing such individuals is often enormous.

Treatment of modifiable factors


Thompson et al suggested that obesity is much more common among asthmatics with severe symptoms, as about 75% of the patients attending an emergency room for asthmatic symptoms were either overweight or obese [10]. Possible factors involved in this relationship include mechanical compression of ventilation with a resultant compromise in functional residual capacity, tidal volume and tidal bronchodilation [11], altered levels of the inflammatory mediators leptin [12] and adinopectin [13], decreased response to inhaled corticosteroids [14] and airway smooth muscle dysfunction [15]. As studies of such individuals indicate that weight loss aids in the symptomatic relief of asthma [16, 17], all obese asthmatics should be advised to lose weight as a part of their management plan.

Allergen exposure

Exposure to environmental, industrial and food allergens plays a crucial role in the pathogenesis of severe asthma. Studies of serum IgE levels to common allergens (cockroaches, house dust mite and Alternaria) show a linear dose-response relationship to asthma morbidity, which includes both increased exacerbations as well as increased need for medication [18]. It is also evident that continual exposure to allergens causes a dramatic decline in lung function by augmenting airway inflammation and remodeling, leading to chronic airway injury that will not effectively respond to pharmacotherapy with corticosteroids [19]. As individuals with severe asthma are already in a compromised state with regards to increased risk of exacerbations and decreased effectiveness of medications, avoidance of all known allergens should be insisted upon. Lifestyle modification like moving to high-altitude locations where there is a lower level of allergens [20] should also be considered.


Research has consistently demonstrated that smoking plays a pivotal role in the development of severe asthma [21 , 22] Individuals presenting to an emergency room for the treatment of asthma were 60% more likely to be smokers than not [22]. Asthmatics who are also smokers, have an enhanced rate of decline in their lung function [23] as well as diminished responsiveness to corticosteroids [24], when compared to their non-smoking counterparts. It is of the utmost importance that these patients abstain from smoking.


Non-steroidal anti-inflammatory drugs (NSAIDs) and -blockers have for long been implicated as triggering factors for the exacerbation of asthma. Aspirin in particular is associated with severe asthma [25] due to perturbations in arachidonic acid metabolism, resulting in an imbalance between pro-inflammatory and anti-inflammatory mediators. Aspirin may also have a stimulatory effect on fibrosis, which can lead to irreversible obstruction and considerably diminished lung function [26]. In a study conducted with 500 asthma patients, 15% were discovered to have aspirin intolerance, of which they were previously unaware, suggesting that provocation tests for aspirin should be performed to detect Aspirin Exacerbated Respiratory Disease (AERD) [27]. Patients with AERD were reported to have a higher incidence of severe asthma (66%) and an increased history of intubation (20%) when compared to their non-aspirin sensitive counterparts [26]. Patients with severe asthma are thus advised to abstain from aspirin and its derivatives although the selective cyclooxygena-se-2 inhibitors celecoxib and etericoxib have been shown to be safe [28, 29]. Additionally, montelukast 10mg daily has been shown to be beneficial in the treatment of aspirin intolerant patients [30, 31].

Another class of drugs that has been incriminated as a trigger factor for asthma exacerbation is -blockers. Bronchoconstriction, through the inhibition of  receptors, was an unacceptable adverse effect of these popular anti-hypertensive drugs and they were thus avoided in asthmatic patients. However, recent evidence indicates that not only are some cardioselective -blockers acceptable for use in asthmatics, but that some, nadalol in particular, have been shown to have a beneficial effect when combined with corticosteroids in the treatment of asthma [32, 33]. However, the decision to start a severe asthmatic on therapy with any -blocker should always be undertaken with extreme caution.


Viral infections, chiefly influenza, play an important role in worsening of the severity of asthma by various mechanisms including increased bronchial hyper-responsiveness, mucus production and airway remodeling [34]. Therefore, influenza vaccinations, which have been demonstrated to be safe in asthmatics, should be administered to all patients with asthma [35, 36].

Similarly, the association between severe asthma and Hepatitis C has been also been pointed out in recent studies [37].

Persistent infections with atypical bacteria are also involved in severe asthma. In a recent study, 52% of patients with severe asthma tested positive for Mycoplasma pneumoniae, demonstrating the importance of the diagnosis and treatment of this infection [38]. Diagnosis should be carried out by polymerase chain reaction (PCR) assays, which have been shown to be the most sensitive test [38] and treatment should be with clarithromycin [39]. Chronic infection with Chlamydia pneumoniae, which is also associated with more severe disease [40, 41], should be tested for and treated with effective medications such as doxycycline, erythromycin or a fluroquinolone [42].


Compliance with medication regimens and treatment plans poses a major problem in the management of severe asthma. Recent evidence indicates that up to 37% of patients with severe asthma admit to being non-compliant and that interventions aimed at improving compliance were able to decrease rates of hospital admission and dosages of prescribed steroids [43]. In-depth patient education [44], electronic monitoring of inhaled steroid use [45] and assessment of prescription filling [46] are methods which, although time consuming, have been demonstrated to improve the adherence to medication and ultimately asthma control. The role of long acting steroids in improving compliance is also of importance, as data suggests that injectable betamethasone [47, 48] and dexamethasone [49, 50] may have a role in the management of asthma. However, as sufficient research on its therapeutic efficacy in severe asthma is not available, further studies are necessary before using them in non-compliant severe asthmatics.

Treatment of co-morbidities

Gastro-esophageal reflux disease (GERD), obstructive sleep apnea (OSA), and sinus diseases are among the most significant co-morbidities associated with severe asthma [51]. One in four asthmatics (25.4%) [52] suffers from GERD, which not only aggravates asthma symptoms, but also increases the frequency of exacerbations. Thus, symptomatic patients should be thoroughly evaluated and treated with acid suppressive therapy, preferably a proton pump inhibitor [53, 54].

Teodorescu et al. reported that the presence of OSA was associated with a 3.6 times higher chance for having poorly controlled asthma [55]. Approximately 63% of children with severe asthma also have OSA [56]. Possible mechanisms associated with the increase in severity include an increase in the level of leukotrienes resulting in bronchospasm. In severe asthmatics, adenotonsillectomy [57, 58] in the pediatric age group and continuous positive airway pressure (CPAP) [59-61] in adults are methods to control OSA.

Both rhinitis and sinusitis are also associated with severe asthma [62] and their treatments have shown to improve lung function in such patients [63, 64].


Conventional therapy

Baseline drugs used to treat the more aggressive forms of asthma include one or more of the following: inhaled corticosteroids (ICS), long acting 2-agonists (LABA), leukotriene modifiers and sustained-release theophyllines [5]. Adding LABA to ICS is widely used as combination drugs and are more effective in improving lung function, asthma symptoms, and decreasing the use of rescue therapy than increasing the dose of ICS alone [65, 66]. When combined, LABA augments the anti-inflammatory action of ICS at a molecular level [67, 68]. In severe asthmatics, when used alone, high doses of ICS are required, reaching up to 1-2 mg/day of beclomethasone dipropionate (BDP), which can lead to serious systemic side effects such as osteoporosis, cataract, and bruising [69, 70]. Thus, newer formulations consisting of smaller particle size preparations of these combination drugs (e.g. beclomethasone and formoterol) have been developed, which are able to reach more distal airways compared to standard preparations, resulting in less absorption from the proximal air passages and fewer systemic side-effects [71]. These new formulations allow much lower doses of both drugs to be used with an equivalent effect on the airways [72].

Leukotriene modifiers suppress the inflammatory process in asthma by decreasing the pro-inflammatory effect of leukotrienes. The leukotriene receptor antagonist, montelukast, usually given at a starting dose of 10 mg/day, is a safe [73] and effective alternative to increasing the dose of ICS and is associated with a significant improvement in morning peak expiratory flow [74]. Montelukast is also particularly effective in asthmatic patients with allergic rhinitis [75]. Zileuton, another modifier, exerts its action by decreasing the amount of leukotriene production through inhibition of the enzyme 5-lipoxygenase. Zileuton is also an effective alternative to increasing the dose of steroids. O’Connor et al. reported a 12% increase in the forced expiratory volume in 1 s (FEV1) when Zileuton 400 mg QID was added to 200 g of BDP given twice daily [76]. However, zileuton has been associated with hepatotoxicity and interacts with drugs such as theophylline and warfarin, and thus should be prescribed cautiously [77].

Theophylline, a methylxanthine and a phosphodiesterase inhibitor has both bronchial smooth muscle relaxation and anti-inflammatory properties. Sustained release theophylline 300-600 mg/day in combination with BDP 250 g BID has been shown to be as effective as 500 g of BDP in increasing the mean morning and evening peak expiratory flow rate (PEFR) as well as the mean FEV1 values in moderate to severe asthmatics [78]. Nevertheless, as it associated with multiple drug interactions and adverse effects [79], patients should be regularly monitored for any untoward consequences from this therapy.

Tiotropium, an anti-cholinergic drug, has also been used as add-on drug in the treatment of severe asthma [80]. In a recent study of severe, uncontrolled asthmatics already receiving ICS and LABA, Kerstjens et al. demonstrated that the addition of once-daily tiotropium (5 g or 10 g) to their usual regimen resulted in a significant improvement in their FEV1 [81].

Despite the treatment options above, physicians are still unable to control asthma in a minority of patients and are forced to keep increasing the doses of their prescribed medications and eventually add oral corticosteroids to their regimen. Prednisone, the most commonly used oral corticosteroid, is administered at doses that are in proportion to the severity of asthma symptoms. Although effective, oral corticosteroids are associated with numerous adverse effects with high doses and long term therapy. Therefore their use is limited and physicians are forced to find steroid-sparing medications to treat such patients.

Cromoglycates like nedocromil and cromolyn sodium while useful in the management of some patients with mild-moderate asthma are not effective enough to be of benefit to patients with severe asthma [4].


Methotrexate, an inhibitor of the enzyme dihydrofolate reductase, is an anti-metabolite used in a variety of immune-mediated diseases. It plays a role in the treatment of severe asthma as a steroid-sparing agent. However, as there is little evidence available regarding the use of methotrexate in severe asthma, its use is controversial. Studies demonstrate that when given at a dose of 10 mg weekly, methotrexate is able to control asthma to the extent of reducing the dose oral corticosteroids by up to 50% [82, 83]. A 6% improvement in FEV1 has also been reported with its use [84]. However, as a variety of gastrointestinal, neurological, hematological, and respiratory side-effects [85] are possible, further studies are required before advocating methotrexate as a safe and effective steroid-sparing agent. It is advised that only physicians with an expertise in severe asthma administer methotrexate with vigilant monitoring throughout its course, using their judgment to decide whether the benefit of methotrexate therapy is worth the risk in each individual patient.

Cyclosporine A is an immunosuppressant drug which acts by inhibiting the release of inflammatory mediators from mast cells and basophils. Studies using a daily dose of 5 mg/kg of cyclosporine have shown a beneficial effect in the treatment of steroid-dependant asthma [86, 87]. Notable benefits of cyclosporine include an improvement in PEFR [88, 89], as well as an increase in FEV1 [88, 90]. However due to the serious side effects [89] such as hirsutism, hypertension and renal impairment, as well as the lack of sufficient experimental data, cyclosporine should be reserved for judicious use in the most serious cases.

Tacrolimus [91], azathioprine [92, 93] and auranofin [94] are other drugs that have been reported to be useful in the treatment of severe asthma. However, sufficient data is not available to affirm their safety and efficacy.

Biological drugs

Omalizumab, a monoclonal antibody directed again IgE, is an effective and well-tolerated drug that can be administered to patients with severe asthma. Studies have demonstrated up to 68% decline in exacerbations with the addition of omalizumab to the treatment regimen of severe asthmatics [95]. In addition to decline in the rate of exacerbations, significantly fewer emergency room visits and improved asthma symptoms have also been reported [96-98]. Administration is via an injection of 0.016 mg/kg per IU/ml of serum IgE [99] and the commonest side effects that have been reported include local injection site reactions and lower respiratory tract infections [97]. However, recent concerns about the development of anaphylaxis with the use of this drug have made physicians cautious about its use.

CD23 is a cell-surface molecule that is thought to influence IgE production. IDEC-152, an IgG1 anti-CD23 antibody has been shown to be safe and decrease serum total IgE in patients with mild-moderate persistent allergic asthma in a phase I, placebo controlled trial. However, after a single dose, there was no significant change in the FEV1 or the PEFR [100].

IgE synthesis is suppressed by inhibition of the cytokines IL-4 and IL-13. Altrakincept, an IL-4 receptor given by inhalation has been shown to be effective and have some steroid-sparing effect in patients with moderate asthma [101]. Pitrakinra, a mutated IL-4 protein that blocks IL-4 and IL-13, when given either by subcutaneous injection or by inhalation has been shown to reduce the response to inhaled allergens in patients with mild asthma [102]. Lebrikizumab, an IL-13 antibody, has been shown to improve lung function in poorly controlled severe asthmatics especially in those that had a high pretreatment level of serum periostin [103].

Mepolizumab, a monoclonal antibody targeting IL-5 has been reported to decrease the number of asthma exacerbations as well as blood and sputum eosinophils, suggesting a unique role in the therapy of the eosinophilic variant of severe asthma [104-106]. Nair et al. demonstrated that a monthly intravenous infusion of 750 mg reduced the requirement of prednisone in as well [107]. However, sufficient data is not available to determine the safety of the drug in severe asthmatics.

Daclizumab, a humanized monoclonal antibody directed against the CD25 subunit of IL-2 receptor, is emerging as a potential agent in the therapy of severe asthma. Busse et al. reported that intravenously administered daclizumab led to improvements in FEV1, daytime asthma symptoms and exacerbation rate [108].

Current studies with etanercept, a TNF- inhibitor, have not shown any benefit in the therapy of severe asthma [109, 110] although perhaps further in-depth studies may prove the drug to be more beneficial. In addition, golimumab, a monoclonal antibody targeting TNF-, was not only shown to have no role in asthma therapy, but also to increase the risk of severe infections and malignancies [111]. At this time, both these drugs are not therapeutic options for asthma.

Antisense oligonucleotides and interference RNA are also coming to light as innovative therapeutic options for asthmatics. These drugs act by targeting RNA transcripts, and consequentially, specific gene products [112, 113]. Currently, EPI-2010 and TPI ASM8 are antisense oligonucleotides which have undergone clinical trials and have been reported to be safe and effective in mild asthmatics [112]. Due to their relative safety, they are drugs which may be effective in severe asthma in the future.

PDE-4 inhibitors

An emerging class of drugs is the phosphodiesterase-4 inhibitors. Their anti-inflammatory action is exerted through enzyme inhibition, resulting in an elevation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels, thereby suppressing inflammation at the cellular level [114]. Two drugs, cilomilast and roflumilast, have been undergoing trials to determine their clinical efficacy in the treatment of asthma. Roflumilast has been shown to have better efficacy and safety profile with tolerable gastrointestinal side effects [115] with evidence supporting its ability to produce improvements in FEV1 and PEFR at a dosage of 100-500 g in patients with mild-moderate asthma [116]. However further trials are necessary to demonstrate its effectiveness in severe asthma.


Currently, clarithromycin is gaining popularity in the treatment of severe asthma over the previously preferred troleandomycin, and is supported by the study conducted by Simpson et al. concluding that clarithromycin therapy, 500 mg twice daily, is able to attenuate IL-8 levels as well as neutrophil activation in severe asthmatics [117]. Additionally, as clarithromycin plays a key role in the treatment of the commonly concomitant infections due to Chlamydophila pneumoniae and Mycoplasma pneumoniae, its antimicrobial property may be beneficial in severe asthma.

Itraconazole, 200 mg twice daily, has been reported to improve the quality of life in those asthmatics that have been sensitized to fungal infections [118].

Miscellaneous therapies

Nebulized heparin has been shown to significantly reduce the late allergic response to allergen in asthmatic subjects which may be due to its anti-inflammatory activity [119].

Oral gold has been to shown to have a small role in decreasing the glucocorticoid dose in steroid-dependent asthmatics [120]. However, this effect is of probably limited clinical significance and given the side-effects of gold and the necessity for monitoring, gold has no role in the treatment of severe asthma.

A variety of other drugs like colchicine, hydroxychloroquine, immunoglobulin, dapsone and Chinese herbal medicines have been used over the years but none of them have ever been shown to have any clear benefit in patients with asthma.

Similarly, dietary alterations like low calorie or elimination diets, magnesium supplementation, diets rich in omega-3 or omega-6 fatty acids and antioxidant supplementation have never been shown to have any benefit in patients with asthma.

Evidence to support other nonpharmacologic interventions like biofeedback and relaxation techniques, acupuncture, chiropractic manipulation, massage therapy and breathing exercises are limited by the absence of well designed clinical trials and therefore cannot be recommended at this time.

Bronchial thermoplasty

Bronchial thermoplasty (BT) is a recently developed bronchoscopic procedure in which radiofrequency energy is used to reduce bronchial smooth muscle wall thickness. In a randomized double-blinded trial, Castro et al. reported that more patients who had undergone BT had an improvement in their Asthma Quality of Life Questionnaire (AQLQ) score compared to those who had not (79% vs. 64%) [121]. Additionally, their study, which consisted of 3 bronchoscopic procedures carried out 3 weeks apart, demonstrated a 32% reduction in the rate of exacerbations in patients who had undergone BT compared to the control group. Immediate adverse effects that occurred include worsening of asthma symptoms and upper respiratory tract infections [121], but studies indicate that in the long term, BT is a safe procedure for severe asthmatics [122]. With the support of more clinical data, BT may eventually become a preferred therapeutic choice in severe asthma.


 1. de Marco R, Cappa V, Accordini S, et al. Trends in the prevalence of asthma and allergic rhinitis in Italy between 1991 and 2010. Eur Respir J 2012; 39: 883-92

 2. Ma J, Xiao L, Knowles SB. Obesity, insulin resistance and the prevalence of atopy and asthma in US adults. Allergy 2010; 65: 1455-63.

 3. Takizawa H. Impact of air pollution on allergic diseases. Korean J Intern Med 2011; 26: 262-73.

 4. Bateman ED, Hurd SS, Barnes PJ, et al. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008; 31: 143-78.

 5. O’Byrne PM. Global guidelines for asthma management: Summary of the current status and future challenges. Pol Arch Med Wewn 2010; 120: 511-7.

6. Antonicelli L, Bucca C, Neri M, et al. Asthma severity and medical resource utilisation. Eur Respir J 2004; 23: 723-9.

7. Herjavecz I, Nagy GB, Gyurkovits K, et al. Cost, morbidity, and control of asthma in hungary: the hunair study. J Asthma 2003; 40: 673-81.

 8. Quirce S, Plaza V, Picado C, Vennera M, Casafont J. Prevalence of uncontrolled severe persistent asthma in pneumology and allergy hospital units in spain. J Investig Allergol Clin Immunol 2011; 21: 466-71.

 9. Siroux V, Pin I, Pison C, Kauffmann F. Severe asthma in the general population: Definition and prevalence. Rev Mal Respir 2004; 21: 961-9.

10. Thomson CC, Clark S, Camargo CA Jr; MARC Investigators. Body mass index and asthma severity among adults presenting to the emergency department. Chest 2003; 124: 795-802.

11. Kent BD, Lane SJ. Twin epidemics: asthma and obesity. Int Arch Allergy Immunol 2011; 157: 213-4.

12. Kilic H, Oguzulgen IK, Bakir F, Turktas H. Asthma in obese women: Outcomes and factors involved. J Investig Allergol Clin Immunol 2011; 21: 290-6.

13. Lugogo NL, Bappanad D, Kraft M. Obesity, metabolic dysregulation and oxidative stress in asthma. Biochim Biophys Acta 2011; 1810: 1120-6.

14. Forno E, Lescher R, Strunk R, et al. Decreased response to inhaled steroids in overweight and obese asthmatic children. J Allergy Clin Immunol 2011; 127: 741-9.

15. Shore SA, Johnston RA. Obesity and asthma. Pharmacol Ther 2006; 110: 83-102.

16. Hernandez Romero A, Matta Campos J, Mora Nieto A, et al. Clinical symptom relief in obese patients with persistent moderate asthma secondary to decreased obesity. Rev Alerg Mex 2008; 55: 103-11.

17. Reddy RC, Baptist AP, Fan Z, Carlin AM, Birkmeyer NJ. The effects of bariatric surgery on asthma severity. Obes Surg 2011; 21: 200-6.

18. Wang J, Visness CM, Calatroni A, Gergen PJ, Mitchell HE, Sampson HA. Effect of environmental allergen sensitization on asthma morbidity in inner-city asthmatic children. Clin Exp Allergy 2009; 39: 1381-9.

19. Di Giampaolo L, Cavallucci E, Braga M, et al. The persistence of allergen exposure favors pulmonary function decline in workers with allergic occupational asthma. Int Arch Occup Environ Health 2012; 85: 181-8.

20. Rijssenbeek-Nouwens LH, Bel EH. High-altitude treatment: a therapeutic option for patients with severe, refractory asthma? Clin Exp Allergy 2011; 41: 775-82.

21. Chapman KR, Boulet LP, Rea RM, Franssen E. Suboptimal asthma control: prevalence, detection and consequences in general practice. Eur Respir J 2008; 31: 320-5.

22. Strine TW, Balluz LS, Ford ES. The associations between smoking, physical inactivity, obesity, and asthma severity in the general US population. J Asthma 2007; 44: 651-8.

23. James AL, Palmer LJ, Kicic E, et al. Decline in lung function in the busselton health study: the effects of asthma and cigarette smoking. Am J Respir Crit Care Med 2005; 171: 109-14.

24. Lazarus SC, Chinchilli VM, Rollings NJ, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007; 175: 783-90.

25. Kupczyk M, Kuprys I, Gorski P, Kuna P. Aspirin intolerance and allergy to house dust mites: important factors associated with development of severe asthma. Ann Allergy Asthma Immunol 2004; 92: 453-8.

26. Mascia K, Haselkorn T, Deniz YM, et al. Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. J Allergy Clin Immunol 2005; 116: 970-5.

27. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE investigators. european network on aspirin-induced asthma. Eur Respir J 2000; 16: 432-6.

28. Martin-Garcia C, Hinojosa M, Berges P, Camacho E, Garcia-Rodriguez R, Alfaya T. Celecoxib, a highly selective COX-2 inhibitor, is safe in aspirin-induced asthma patients. J Investig Allergol Clin Immunol 2003; 13: 20-5.

29. Sanchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A. Safety of etoricoxib, a new cyclooxygenase 2 inhibitor, in patients with nonsteroidal anti-inflammatory drug-induced urticaria and angioedema. Ann Allergy Asthma Immunol 2005; 95: 154-8.

30. Micheletto C, Tognella S, Visconti M, Pomari C, Trevisan F, Dal Negro RW. Montelukast 10 mg improves nasal function and nasal response to aspirin in ASA-sensitive asthmatics: a controlled study vs placebo. Allergy 2004; 59: 289-94.

31. Dahlen SE, Malmstrom K, Nizankowska E, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165: 9-14.

32. Hanania NA, Singh S, El-Wali R, et al. The safety and effects of the beta-blocker, nadolol, in mild asthma: an open-label pilot study. Pulm Pharmacol Ther 2008; 21: 134-41.

33. Nguyen LP, Singh B, Okulate AA, et al. Complementary anti-inflammatory effects of a beta-blocker and a corticosteroid in an asthma model. Naunyn Schmiedebergs Arch Pharmacol 2012; 385: 203-10.

34. Kloepfer KM, Gern JE. Virus/allergen interactions and exacerbations of asthma. Immunol Allergy Clin North Am 2010; 30: 553-63, vii.

35. Busse WW, Peters SP, Fenton MJ, et al. Vaccination of patients with mild and severe asthma with a 2009 pandemic H1N1 influenza virus vaccine. J Allergy Clin Immunol 2011; 127: 130-7, 137.e1-3.

36. Vaughn JA, Miller RA. Update on immunizations in adults. Am Fam Physician 2011; 84: 1015-20.

37. Nakashima T, Yokoyama A, Ohnishi H, et al. Chronic hepatitis C virus infection is associated with more severe asthma. Allergol Int 2011; 60: 299-304.

38. Peters J, Singh H, Brooks EG, et al. Persistence of community-acquired respiratory distress syndrome toxin-producing mycoplasma pneumoniae in refractory asthma. Chest 2011; 140: 401-7.

39. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and chlamydia pneumoniae in asthma: Effect of clarithromycin. Chest 2002; 121: 1782-8.

40. Specjalski K, Jassem E. Chlamydophila pneumoniae, mycoplasma pneumoniae infections, and asthma control. Allergy Asthma Proc 2011; 32: 9-17.

41. Black PN, Scicchitano R, Jenkins CR, et al. Serological evidence of infection with chlamydia pneumoniae is related to the severity of asthma. Eur Respir J 2000; 15: 254-9.

42. Horiguchi T, Miyazaki J, Ohira D, et al. Usefulness of sparfloxacin against chlamydia pneumoniae infection in patients with bronchial asthma. J Int Med Res 2005; 33: 668-76.

43. Gamble J, Stevenson M, Heaney LG. A study of a multi-level intervention to improve non-adherence in difficult to control asthma. Respir Med 2011; 105: 1308-15.

44. Dalcin Pde T, Grutcki DM, Laporte PP, et al. Impact of a short-term educational intervention on adherence to asthma treatment and on asthma control. J Bras Pneumol 2011; 37: 19-27.

45. Apter AJ, Wang X, Bogen DK, et al. Problem solving to improve adherence and asthma outcomes in urban adults with moderate or severe asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128: 516-23.e1-5.

46. Heaney LG, Horne R. Non-adherence in difficult asthma: time to take it seriously. Thorax 2012; 67: 268-70.

47. Mazzei CM, Lasala FG, Ambrosio JA. The effect of betamethasone dipropionate injectable on chronic bronchial asthma. J Int Med Res 1981; 9: 138-42.

48. Chan JS, Cowie RL, Lazarenko GC, Little C, Scott S, Ford GT. Comparison of intramuscular betamethasone and oral prednisone in the prevention of relapse of acute asthma. Can Respir J 2001; 8: 147-52.

49. Gries DM, Moffitt DR, Pulos E, Carter ER. A single dose of intramuscularly administered dexamethasone acetate is as effective as oral prednisone to treat asthma exacerbations in young children. J Pediatr 2000; 136: 298-303.

50. Bhatnagar SK. Can single dose intramuscular dexamethasone replace five day oral prednisolone therapy in mild to moderate asthma cases? Indian Pediatr 2000; 37: 1158-9.

51. Butler C, Heaney LG. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J 2006; 27: 1324-5.

52. Bor S, Kitapcioglu G, Solak ZA, Ertilav M, Erdinc M. Prevalence of gastroesophageal reflux disease in patients with asthma and chronic obstructive pulmonary disease.

J Gastroenterol Hepatol 2010; 25: 309-13.

53. Lee YB, Lim JH, Choi YJ, et al. Effects of proton pump inhibitors in asthmatics with gastroesophageal reflux disease. Korean J Gastroenterol 2011; 58: 178-83.

54. Sharma B, Sharma M, Daga MK, Sachdev GK, Bondi E. Effect of omeprazole and domperidone on adult asthmatics with gastroesophageal reflux. World J Gastroenterol 2007; 13: 1706-10.

55. Teodorescu M, Polomis DA, Hall SV, et al. Association of obstructive sleep apnea risk with asthma control in adults. Chest 2010; 138: 543-50.

56. Kheirandish-Gozal L, Dayyat EA, Eid NS, Morton RL, Go-zal D. Obstructive sleep apnea in poorly controlled asthmatic children: effect of adenotonsillectomy. Pediatr Pulmonol 2011; 46: 913-8.

57. Malakasioti G, Gourgoulianis K, Chrousos G, Kaditis A. Interactions of obstructive sleep-disordered breathing with recurrent wheezing or asthma and their effects on sleep quality. Pediatr Pulmonol 2011; 46: 1047-54.

58. Bhattacharjee R, Kheirandish-Gozal L, Spruyt K, et al. Adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study. Am J Respir Crit Care Med 2010; 182: 676-83.

59. Brzecka A, Pawelec-Winiarz M, Piesiak P, Nowak E, Jankowska R. Suppression of chronic nocturnal cough during continuous positive airway pressure (CPAP) treatment in a patient with asthma and obstructive sleep apnea syndrome. Pneumonol Alergol Pol 2011; 79: 121-6.

60. Lafond C, Series F, Lemiere C. Impact of CPAP on asthmatic patients with obstructive sleep apnoea. Eur Respir J 2007; 29: 307-11.

61. Xue Z, Yu Y, Gao H, Gunst SJ, Tepper RS. Chronic continuous positive airway pressure (CPAP) reduces airway reactivity in vivo in an allergen-induced rabbit model of asthma. J Appl Physiol 2011; 111: 353-7.

62. Boulet LP, Boulay ME. Asthma-related comorbidities. Expert Rev Respir Med 2011; 5: 377-93.

63. Dixon AE, Kaminsky DA, Holbrook JT, Wise RA, Shade DM, Irvin CG. Allergic rhinitis and sinusitis in asthma: differential effects on symptoms and pulmonary function. Chest 2006; 130: 429-35.

64. Castillo Vizuete JA, Mullol Miret J. Rhinitis and asthma comorbidity in spain: the RINAIR study. Arch Bronconeumol 2008; 44: 597-603.

65. Greenstone IR, Ni Chroinin MN, Masse V, et al. Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma. Cochrane Database Syst Rev 2005; 4: CD005533.

66. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev 2010; 4: CD005533.

67. Kaur M, Chivers JE, Giembycz MA, Newton R. Long-acting beta2-adrenoceptor agonists synergistically enhance glucocorticoid-dependent transcription in human airway epithelial and smooth muscle cells. Mol Pharmacol 2008; 73: 203-14.

68. Chung KF, Caramori G, Adcock IM. Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future. Eur J Clin Pharmacol 2009; 65: 853-71.

69. Dahl R. Systemic side effects of inhaled corticosteroids in patients with asthma. Respir Med 2006; 100: 1307-17.

70. Rossi GA, Cerasoli F, Cazzola M. Safety of inhaled corticosteroids: room for improvement. Pulm Pharmacol Ther 2007; 20: 23-35.

71. Scichilone N, Battaglia S, Sorino C, et al. Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthma. Allergy 2010; 65: 897-902.

72. Paggiaro P. New pharmacologic perspectives in pneumology: beclomethasone-formoterol extrafine. Open Respir Med J 2009; 3: 38-42.

73. Diamant Z, Mantzouranis E, Bjermer L. Montelukast in the treatment of asthma and beyond. Expert Rev Clin Immunol 2009; 5: 639-58.

74. Price DB, Hernandez D, Magyar P, et al. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose inhaled budesonide in adult patients with asthma. Thorax 2003; 58: 211-6.

75. Amlani S, Nadarajah T, McIvor RA. Montelukast for the treatment of asthma in the adult population. Expert Opin Pharmacother 2011; 12: 2119-28.

76. O’Connor BJ, Lofdahl CG, Balter M, Szczeklik A, Boulet LP, Cairns CB. Zileuton added to low-dose inhaled beclomethasone for the treatment of moderate to severe persistent asthma. Respir Med 2007; 101: 1088-96.

77. Mastalerz L, Kumik J. Antileukotriene drugs in the treatment of asthma. Pol Arch Med Wewn 2010; 120: 103-8.

78. Wang Y, Wang CZ, Lin KX, et al. Comparison of inhaled corticosteroid combined with theophylline and double-dose inhaled corticosteroid in moderate to severe asthma. Respirology 2005; 10: 189-95.

79. Makino S, Adachi M, Ohta K, et al. A prospective survey on safety of sustained-release theophylline in treatment of asthma and COPD. Allergol Int 2006; 55: 395-402.

80. Kapoor AS, Olsen SR, O’Hara C, Puttagunta L, Vethanayagam D. The efficacy of tiotropium as a steroid-sparing agent in severe asthma. Can Respir J 2009; 16: 99-101.

81. Kerstjens HA, Disse B, Schroder-Babo W, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol 2011; 128: 308-14.

82. Domingo Ribas C, Comet Monte R, Bosque Garcia M, Moron Besoli A, Monton Soler C. Efficiency of methotrexate in the treatment of cortico-dependent asthmatic patients. Rev Clin Esp 1999; 199: 142-6.

83. Comet R, Domingo C, Larrosa M, et al. Benefits of low weekly doses of methotrexate in steroid-dependent asthmatic patients. A double-blind, randomized, placebo-controlled study. Respir Med 2006; 100: 411-9.

84. Aaron SD, Dales RE, Pham B. Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomized clinical trials. Respir Med 1998; 92: 1059-65.

85. Attar SM. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. A hospital-based study. Saudi Med J 2010; 30: 909-15.

86. Coren ME, Rosenthal M, Bush A. The use of cyclosporin in corticosteroid dependent asthma. Arch Dis Child 1997; 77: 522-3.

87. Balfour-Lynn I. Difficult asthma: beyond the guidelines. Arch Dis Child 1999; 80: 201-6.

 88. Alexander AG, Barnes NC, Kay AB. Trial of cyclosporin in corticosteroid-dependent chronic severe asthma. Lancet 1992; 339: 324-8.

 89. Lock SH, Kay AB, Barnes NC. Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 1996; 153: 509-14.

 90. Mungan D, Misirligil Z, Sin B, Kaya A, Demirel Y, Gurbuz L. Cyclosporin in steroid dependent asthma. Allergol Immunopathol (Madr) 1995; 23: 202-6.

 91. Taniguchi H, Tokui K, Iwata Y, Abo H, Izumi S. A case of severe bronchial asthma controlled with tacrolimus. J Allergy (Cairo) 2011; 2011: 479129.

 92. Saadeh C, Urban RS. Azathioprine in the treatment of chronic refractory steroid-dependent asthma. South Med J 1993; 86: 94-5.

 93. Dean T, Dewey A, Bara A, Lasserson TJ, Walters EH. Azathioprine as an oral corticosteroid sparing agent for asthma. Cochrane Database Syst Rev 2004; 1: CD003270.

 94. Bernstein IL, Bernstein DI, Dubb JW, Faiferman I, Wallin B. A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma auranofin multicenter drug trial. J Allergy Clin Immunol 1996; 98: 317-24.

 95. Korn S, Schumann C, Kropf C, et al. Effectiveness of omalizumab in patients 50 years and older with severe persistent allergic asthma. Ann Allergy Asthma Immunol 2010; 105: 313-9.

 96. Niven R, Chung KF, Panahloo Z, Blogg M, Ayre G. Effectiveness of omalizumab in patients with inadequately controlled severe persistent allergic asthma: an open-label study. Respir Med 2008; 102: 1371-8.

 97. Humbert M, Beasley R, Ayres J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005; 60: 309-16.

 98. Brusselle G, Michils A, Louis R, et al. “Real-life” effectiveness of omalizumab in patients with severe persistent allergic asthma: the PERSIST study. Respir Med 2009; 103: 1633-42.

 99. Bang LM, Plosker GL. Omalizumab: a review of its use in the management of allergic asthma. Treat Respir Med 2004; 3: 183-99.

100. Rosenwasser LJ, Busse WW, Lizambri RG, Olejnik TA, Totoritis MC. Allergic asthma and an anti-CD23 mAb (IDEC-152): results of a phase I, single-dose, dose-escalating clinical trial. J Allergy Clin Immunol 2003; 112: 563.

101. Borish LC, Nelson HS, Lanz MJ, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 1999; 160: 1816.

102. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007; 370: 1422.

103. Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med 2011; 365: 1088.

104. Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009; 360: 973-84.

105. Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007; 176: 1062-71.

106. Busse WW, Ring J, Huss-Marp J, Kahn JE. A review of treatment with mepolizumab, an anti-IL-5 mAb, in hypereosinophilic syndromes and asthma. J Allergy Clin Immunol 2010; 125: 803-13.

107. Nair P, Pizzichini MM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009; 360: 985-93.

108. Busse WW, Israel E, Nelson HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008; 178: 1002-8.

109. Holgate ST, Noonan M, Chanez P, et al. Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial. Eur Respir J 2011; 37: 1352-9.

110. Morjaria JB, Chauhan AJ, Babu KS, Polosa R, Davies DE, Holgate ST. The role of a soluble TNFαlpha receptor fusion protein (etanercept) in corticosteroid refractory asthma: a double blind, randomised, placebo controlled trial. Thorax 2008; 63: 584-91.

111. Wenzel SE, Barnes PJ, Bleecker ER, et al. A randomized, double-blind, placebo-controlled study of tumor necrosis factor-alpha blockade in severe persistent asthma. Am J Respir Crit Care Med 2009; 179: 549-58.

112. Ball HA, Van Scott MR, Robinson CB. Sense and antisense: therapeutic potential of oligonucleotides and interference RNA in asthma and allergic disorders. Clin Rev Allergy Immunol 2004; 27: 207-17.

113. Sandrasagra A, Tang L, Leonard SA, et al. RASONs: a novel antisense oligonucleotide therapeutic approach for asthma. Expert Opin Biol Ther 2001; 1: 979-83.

114. Fan Chung K. Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol 2006; 533: 110-7.

115. Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005; 365: 167-75.

116. Bateman ED, Izquierdo JL, Harnest U, et al. Efficacy and safety of roflumilast in the treatment of asthma. Ann Allergy Asthma Immunol 2006; 96: 679-86.

117. Simpson JL, Powell H, Boyle MJ, Scott RJ, Gibson PG. Clarithromycin targets neutrophilic airway inflammation in refractory asthma. Am J Respir Crit Care Med 2008; 177: 148-55.

118. Denning DW, O’Driscoll BR, Powell G, et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: the fungal asthma sensitization trial (FAST) study. Am J Respir Crit Care Med 2009; 179: 11-8.

119. Diamant Z, Timmers MC, van der Veen H, Page CP, van der Meer FJ, Sterk PJ. Effect of inhaled heparin on allergen-induced early and late asthmatic responses in patients with atopic asthma. Am J Respir Crit Care Med 1996; 153: 1790.

120. Evans DJ, Cullinan P, Geddes DM. Gold as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001; 2: CD002985.

121. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010; 181: 116-24.

122. Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006; 173: 965-9.
Copyright: © 2012 Termedia & Banach. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Quick links
© 2020 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe